Hyperlipidemia and COPD: 2 Old Problems with New Therapies ... · Hyperlipidemia and COPD: 2 Old Problems with New Therapies and Goals Activity Number: ... Many Patients Do Not Achieve

Hyperlipidemia and COPD: 2 Old Problems with New Therapies and Goals Activity Number: 0217-0000-16-116-L01-P 1.50 hours of CPE credit; Activity Type: An Application-Based Activity

Monday, October 24, 2016 9:15 a.m. to 10:45 a.m. Great Hall 3

Moderator: E. Kelly Hester, Pharm. D., FCCP, BCPS Associate Clinical Professor, Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, Auburn, Alabama

Agenda

9:15 a.m. Is 50 the New 70? Exploring the Value of Intensified LDL reduction with PCSK-9 Inhibitors and Ezetimibe Tran H. Tran, Pharm. D., BCPS Associate Professor, Midwestern University, Chicago College of Pharmacy, Downers Grove, Illinois

10:00 a.m. Update in COPD Pharmacotherapy: Is New Better? Christopher K. Finch, Pharm. D., BCPS Director of Pharmacy, Methodist University Hospital; Associate Professor, University of Tennessee College of Pharmacy, Memphis, Tennessee

Conflict of Interest Disclosures

Christopher K. Finch: no conflicts to disclose E. Kelly Hester: no conflicts to discloseTran H. Tran: no conflicts to disclose

Learning Objectives 1. Explain the relationship between serum LDL level and residual cardiovascular diseases.2. Evaluate the literature describing the use of the PSCK-9 inhibitors for reducing cardiovascular disease.3. Interpret the literature pertaining the use of ezetimibe for reducing cardiovascular disease.4. Construct an evidence-based pharmacotherapy regimen for reducing residual cardiovascular disease in

at risk patients.5. Compare and contrast the pharmacological and cost differences with new therapy options for COPD

compared to older medications.6. Discuss the evidence-based outcomes of newer pharmacologic options based on clinical trials

compared to older medications.7. Explain the role of new agents in the medical management of COPD.

Self-Assessment Questions

Self-assessment questions are available online at www.accp.com/am

© American College of Clinical Pharmacy 1

http://www.accp.com/am

2016 ACCP Annual Meeting

Is 50 the new 70? Exploring the value of intensified LDL reduction with PCSK‐9 inhibitors and ezetimibe

Tran H. Tran, Pharm. D., BCPSAssociate Professor

Midwestern University Chicago College of Pharmacy

Downer’s Grove, ILOctober 24, 2016



Conflict of Interest

• None to disclose



Learning Objectives Explain the relationship between serum LDL level and residual cardiovascular diseases. Evaluate the literature describing the use of the PCSK‐9 inhibitors for reducing cardiovascular disease. Interpret the literature pertaining to the use of ezetimibe for reducing cardiovascular disease.Construct an evidence‐based pharmacotherapy regimen for reducing residual cardiovascular disease in at risk patients.



CVD Remains an Area of High Unmet Need• CVD remains the leading cause of death in the US accounting for 1 out of every 7 deaths

• Costs > $320 billion each year

High Morbidity, Mortality, and Cost

• Despite effective treatments like statins, many patients are not achieving optimal LDL‐C levels

Suboptimal LDL Management

• Statin intolerance occurs in ~ 10–20% of patients and commonly results in treatment discontinuationStatin Intolerance

• Beyond statins, existing nonstatin agents provide only modest LDL‐C reduction

Limited Treatment Options

CVD = cardiovascular disease; LDL = low‐density lipoprotein; LDL‐C = LDL‐cholesterol.Mozaffarian D, et al. Circulation. 2015; 131(4):e29‐322; CDC. Heart Disease Facts. www.cdc.gov/heartdisease/facts.htm. Accessed 3/24/15; Go AS, et al. Circulation. 2014;129(3):E28‐E292; Rosenson RS, et al. J Clin Lipidol. 2014;8(3 Suppl):S58‐S71. PRIME®.



ACC/AHA 2013 Guidelines: 4 Statin Benefit Groups and Intensity of Statin Therapy

• Age ≤ 75: High‐intensity statin• Age > 75: Moderate‐intensity statin

Secondary Prevention Clinical ASCVD

• High‐intensity statinPrimary PreventionLDL‐C ≥ 190 mg/dL

• Low risk (10‐year risk < 7.5%): Moderate‐intensity statin• High risk (10‐year risk ≥ 7.5%): High‐intensity statin

Primary PreventionAge 40–75 with diabetes and LDL 70–189 mg/dL, no clinical ASCVD

• Consider moderate‐ or high‐intensity statin

Primary Prevention Age 40–75 with no diabetes or

clinical ASCVD, LDL 70–189 mg/dL, estimated 10‐year ASCVD ≥ 7.5%

Stone NJ, et al. Circulation. 2013;129(25 Suppl 2):S1‐S45.



Despite Treatment with High‐Dose Statins, Many Patients Do Not Achieve Goal*

Distribution of Achieved LD

L‐C Levels (%

)

Hazard Ra

tio (H

R; %)

LDL‐C (mg/dL)

10

20

30

020015010050

0

0.50

0.75

1.00

0.25

250

40

*< 70 mg/dLAdapted from: Boekholdt SM, et al. J Am Coll Cardiol. 2014;64(5):485‐494. PRIME®.

LDL‐C levels

Risk of major CV events

On‐Statin LDL‐C Levels and Risk of Major Cardiovascular Events



PCSK9 inhibitors



Heterozygous FH• Characterized by high LDLC levels (≥ 190 mg/dL)• Primarily caused by mutations in LDL‐R gene, as well as in APOB or PCSK9 genes

• Believed to occur in one in every 200 individuals• Leads to 10‐ to 20‐fold lifetime increased risk of heart attack

• Men with HeFH have a 50% chance of a heart attack by age 50 without treatment and in women there’s a 30% chance by age 60

HeFH = heterozygous familial hypercholesterolemia, LDLC = LDL cholesterol, LDL‐R = LDL‐receptor.



PCSK9: A Compelling New Hypercholesterolemia Target

• The key role of PCSK9 in LDL‐C metabolism:

• Promotes intracellular degradation of hepatic LDL‐R

• Prevents LDL‐R recycling to cell surface

• Reduces LDL‐R population on cell surface

• Reduces LDL clearance from circulation

LDL‐R = LDL‐receptor.Lambert G, et al. J Lipid Res. 2012;53(12):2515‐2524.



Role of PCSK9 in Regulation of LDL‐R Expression



FDA Approved PCSK9 Inhibitors:Alirocumab Evolocumab

IndicationPatients with HeFH or clinical atherosclerotic CVD

In addition to diet and maximally tolerated statin therapy

Dosage and administration

• Two different doses: 75 mg or 150 mg dose every 2 weeks

• Available in a single 1 mL SQ injection delivered in a single‐dose prefilled pen or syringe that patients self‐administer

• Two different doses: 140 mg dose every 2 weeks or 420 mg dose every month

• Available in a single prefilled SQ autoinjector or on‐body infusor with prefilled cartridge

HeFH = heterozygous familial hypercholesterolemia, CVD = cardiovascular diseaseFDA News Release. FDA approves Praluent to treat certain patients with high cholesterol. Released July 24, 2015. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm



Alirocumab: ODYSSEY Trial ProgramType of Study Trial Name N Duration (weeks)

Moderate CV Risk MONO 103 24

Statin Intolerant ALTERNATIVE 314 24

High LDL‐C

High CV Risk

CHOICE II*

CHOICE I*

OPTIONS I

OPTIONS II

COMBO I

COMBO II

LONGTERM

803

233

355

305

316

720

2,341

24

24

52

104

52

24

78

HeFHFH I

FH II

High FH

471

250

105

78

78

78

High CV Risk

Recent CV EventOUTCOMES 18,000 5–6 years Ongoing

Plus max statin dose

Not receiving statins

Moderate statin dose

*CHOICE I & II evaluated alirocumab every 2 weeks and monthly.; PRIME®.



Alirocumab: ODYSSEY LONGTERM Study Design

Placebo SC Q2W

R

W4 W12 W24 W52 W64 W78

W0 W8 W16 W36Assessments

Double‐Blind Treatment (18 months)Follow‐up (8 weeks)

Primary efficacy endpoint

Pre‐specified analysisEfficacy endpoints: All patients up to W52 on the ITT analysis and population Safety analysis: All patients randomized and treated whatever the duration of exposure

N = 1,553

N = 788

Robinson JG, et al. N Engl J Med. 2015;372(16):1489‐1499.; PRIME®.

HeFH or high CV risk patients on maximally tolerated statin +/‐other lipid‐lowering

therapyLDL‐C ≥ 70 mg/dL

Alirocumab 150 mg SC Q2W Administered via single 1 mL injection using prefilled pen for self‐injection



Alirocumab (ODYSSEY LONGTERM) Calculated LDL‐C Levels Over Time (ITT)

Least‐Squa

res M

ean Ca

lculated

LDL‐C Level (mg/dL)

Time (weeks)4 8 12 16 24 52 64 78

20

40

60

80

100

120

140

0.00

0.60

1.20

2.40

3.00

3.60

1.80

‐52.4%*

57.9 mg/dL (1.50 mmol/liter)



Placebo + statin therapy at maximum tolerated dose +/‐ LLTAlirocumab + statin therapy at maximum tolerated dose +/‐ LLT

(mmol/liter)

3600

*P < 0.001 LLT = lipid‐lowering therapy. Robinson JG, et al. N Engl J Med. 2015;372(16):1489‐1499; PRIME®.


‐0.8%

‐61.0%*

‐3.6%



Alirocumab (ODYSSEY LONGTERM) Safety Analysis

Summary of AEsAlirocumab(n = 1,550)

Placebo(n = 788) P Value

SAEs 290 (18.7%) 154 (19.5%) 0.66

AE leading to discontinuation 111 (7.2%) 46 (5.8%) 0.26

AE leading to death 8 (0.5%) 10 (1.3%) 0.08

General allergic reaction events 156 (0.1%) 75 (9.5%) 0.71

Treatment‐related injection site reactions 91 (5.9%) 33 (4.2%) 0.10

Neurologic events 65 (4.2%) 35 (4.4%) 0.83

Neurocognitive events 18 (1.2%) 4 (0.5%) 0.17

Robinson JG, et al. N Engl J Med. 2015;372(16):1489‐1499. PRIME®.

Among patients who received alirocumab, 575 (37.1%) had a calculated LDL‐C level of < 25 mg/dL at 2 consecutive measurements. Rates of AEs were similar to those in the overall alirocumab group.



Alirocumab (ODYSSEY LONGTERM)Safety Analysis: Cardiovascular Adverse EventsCardiovascular AE Alirocumab

(n = 1,550)Placebo(n = 788) P Value

CHD death 4 (0.3%) 7 (0.9%) 0.26

Non‐fatal MI 14 (0.9%) 18 (2.3%) 0.01

Fatal + non‐fatal ischemic stroke 9 (0.6%) 2 (0.3%) 0.35

Unstable angina requiring hospitalization 0 1 (0.1%) 0.34

Positively adjudicated CV events, including all those listed above 72 (4.6%) 40 (5.1%) 0.68

Adjudicated major AEs in post‐hoc analysis* 27 (1.7%) 26 (3.3%) 0.02

*The post‐hoc analysis was not specified in the study protocol. It included the following CV event categories, which also form the endpoint for the ODYSSEY OUTCOMES study: Death from CHD, non‐fatal MI, fatal and non‐fatal ischemic stroke, and unstable angina requiringhospitalization. “Unstable angina requiring hospitalization” is limited to the unstable angina events with definite evidence of progression of the ischemic condition (strict criteria). Robinson JG, et al. N Engl J Med. 2015;372(16):1489‐1499; PRIME®.



Post‐Hoc Analysis of a Subgroup of Adjudicated Major Adverse Cardiovascular Events*

0.00

0.02

0.04

0.06

0 12 24 52 64 78 8636

0.6

0.4

0. 2

0.8

1.0

0.0

0 12 24 36 52 64 78 86

Cumulative Prob

ability of Event (%

)

Time (weeks)

Cox model analysis HR = 0.52 (95% CI 0.31–0.90)

Nominal P value ≤ 0.01

*same primary endpoint as ongoing ODYSSEY OUTCOMES trial.Robinson JG, et al. N Engl J Med. 2015;372(16):1489‐1499. PRIME®.

No. at Risk

Placebo 788 776 731 700 670 653 644 597

Alirocumab 1550 1533 1445 1392 1342 1306 1266 1170

Placebo + statin therapy at maximum tolerated dose +/‐ LLT

Alirocumab + statin therapy at maximum tolerated dose +/‐ LLT

Placebo

Alirocumab



Evolocumab: Select Trials from the PROFICIO Clinical Trial Program*

Type of Study Trial Name N Duration(weeks)

Monotherapy MENDEL‐2 614 12

Statin IntolerantGAUSS‐2GAUSS‐3

307500;100

12

24 Ongoing

Combination Therapy LAPLACE‐2 1,896 12

High CV Risk DESCARTES 901 52

GLAGOV 950 78 Ongoing

FHRUTHERFORD‐2 (HeFH)

TESLA (HoFH)

TAUSSIG

329

58

250

12

12

5 years Ongoing

Established CVD FOURIER 22,500 5 years Ongoing

Not Receiving Statins

Receiving Statin Therapy

*Evaluated evolocumab every 2 weeks and monthly.PRIME®.



Evolocumab: Open‐Label Studies of Long‐Term Evaluation Against (OSLER‐1 and OSLER‐2)

Standard of Care Alone

(n = 1,489)

Evolocumab + Standard of Care

(n = 2,976)

MENDEL‐1 (n = 406)

MENDEL‐2 (n = 614)

Phase 2 trials

Phase 3 trialsTHOMAS‐1(n = 149)

THOMAS‐2(n = 164)

LAPLACE‐TIMI 57 (n = 629)

LAPLACE‐2 (n = 1,896)

GAUSS‐2(n = 307)

GAUSS‐1(n = 157)

RUTHERFORD‐1(n = 167)

RUTHERFORD‐2(n = 329)

YUKAWA‐1(n = 307)

DESCARTES(n = 901)

Sabatine MS, et al. N Engl J Med. 2015;372(16):1500‐1509. PRIME®.

4,465 patients (74%) elected to enroll into OSLER extension study program1,324 from phase 2 trials into OSLER‐13,141 from phase 3 trials into OSLER‐2

Eligible if medically stable and on study drug

Randomized 2:1

Irrespective of treatment assignment in parent study



Evolocumab (OSLER‐1 and OSLER‐2): LDL‐C Levels Over Time

No. at Risk

Standard therapy 1489 394 1388 1376 402 1219

Evolocumab 2976 864 2871 2828 841 2508

Absolute reduction (mg/dL) 60.4 73.4 70.4 72.7 70.5

Percentage reduction 56.3 60.9 58.8 54.0 58.4

P value < 0.001 < 0.001 < 0.001 < 0.001 < 0.001

Baseline 4 12 24 36 48

Evolocumab + Standard of Care

Standard of Care

20

40

60

80

100

120

140LD

L‐C (m

g/dL)

0

Time (weeks)




Evolocumab (OSLER‐1 and OSLER‐2)Safety Analysis

Evolocumab + Standard of Care(n = 2,976)

Standard of CareAlone

(n = 1,489)

SAEs 222 (7.5%) 111 (7.5%)

AEs leading to discontinuation of evolocumab 71 (2.4%) NA

Muscle‐related 190 (6.4%) 90 (6.0%)

Injection‐site reaction 129 (4.3%) NA

Neurocognitive event 27 (0.9%) 4 (0.3)




Evolocumab (OSLER‐1 and OSLER‐2)Patient Incidence of Cardiovascular Clinical Events

Endpoint

Evolocumab +Standard Therapy

(n = 2,976)

Standard TherapyAlone

(n = 1,489)

HR (95% CI)

All CV events 29 (0.95%) 31 (2.18%) 0.47 (0.28–0.78)

Death 4 (0.14%) 6 (0.41%) 0.33(0.09–1.18)

Coronary events(MI, hospitalization for unstable angina, coronary revascularization)

22 (0.75%) 18 (1.30%) 0.61(0.33–1.14)

Cerebrovascular events (stroke or TIA) 4 (0.14%) 7 (0.47%) 0.29

(0.08–0.98)

Heart failure requiring hospitalization 1 (0.03%) 1 (0.07%) 0.52

(0.03–8.30)Sabatine MS, et al. N Engl J Med. 2015;372(16):1500‐1509. PRIME®.



Evolocumab (OSLER‐1 and OSLER‐2)Cumulative Incidence of Cardiovascular Events




LDL‐C reduction with PCSK9 inhibitors• Long‐term effects of very low levels of LDL‐C induced by PCSK9 inhibitors are unknown

• Effect on cardiovascular morbidity and mortality has not been determined.

• Potential for immunogenicity• Safety and effectiveness not established in pediatric patients with primary hyperlipidemia or HeFH

LDL‐C = low density lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia



LDL‐C reduction a reliable surrogate for cardiovascular outcomes?

• Statin approvals based on the LDL cholesterol surrogate (1987)

• Ezetimibe approval based on LDL cholesterol surrogate (2002)

• Nonstatin trials did not support correlation • ILLUMINATE study• HPS2‐THRIVE



What Can We Learn from IMPROVE‐IT?Ezetimibe/Simvastatin vs Simvastatin



IMPROVE‐IT: Ezetimibe/Simvastatin vs Simvastatin• Large scale (N = 18,144) RCT of high‐risk post‐ACS patients

• Intervention: Ezetimibe 10 mg added to simvastatin 40 mg• Comparator: Simvastatin 40 mg

• Simvastatin dose uptitrated to 80 mg in patients with LDL‐C > 79 mg/dL

• 27% in simvastatin group and 6% in ezetimibe/simvastatin group

• Primary endpoint: • Composite of cardiovascular death, MI, unstable angina requiring hospitaliziation, coronary revascularization, or stroke

• Study took 9 years; follow‐up was 7 years

ACS = acute coronary syndrome. Cannon CP, et al. N Engl J Med 2015;372(25):2387‐2397. PRIME®.



IMPROVE‐IT: LDL‐C and Lipid Changes

QE 1R 9648 60 72 84124 8 2416 36

40

50

60

70

80

90

100

Mean LD

L‐C (m

g/dL)

Median Time avg69.5 vs 53.7 mg/dL

1‐yr Mean LDL‐C TC TG HDL hsCRP

Simvastatin 69.9 145.1 137.1 48.1 3.8

EZ/Simva 53.2 125.8 120.4 48.7 3.3

∆ in mg/dL ‐16.7 ‐19.3 ‐16.7 +0.6 ‐0.5

Time Since Randomization (months)

TC = total cholesterol; TG = triglycerides; hsCRP = high sensitivity C‐reactive protein. Cannon CP, et al. N Engl J Med 2015;372(25):2387‐2397. PRIME®.

Ezetimibe/SimvastatinSimvastatin



IMPROVE‐IT: Results for Primary Endpoint*

32.7%34.7%

0%

10%

20%

30%

40%

50%% Sub

jects who

Experienced

an Even

t2% Absolute Risk Reduction

*The primary composite endpoint was CV death, nonfatal myocardial infarction (MI), nonfatal stroke, rehospitalization for unstable angina (UA), and coronary revascularization (≥ 30 days postrandomization). Cannon CP, et al. N Engl J Med 2015;372(25):2387‐2397. PRIME®.

HR = 0.936P = 0.016NNT = 50

Simvastatin 40 mg (n = 9,077)

Ezetimibe 10 mg / Simvastatin 40 mg

(n = 9,067)

2,572 events 2,742 events



IMPROVE‐IT: Individual Primary and Secondary Endpoints (7‐year event rates)

Clinical OutcomesSimvastatin n = 9,077 (%)

Ezetimibe/Simvastatin n = 9,067 (%) P Value

All‐cause death 15.3 15.4 0.782

MI 14.8 13.1 0.002

Stroke 4.8 4.2 0.052

Ischemic stroke 4.1 3.4 0.008

Unstable angina 1.9 2.1 0.618

Coronary revascularization 23.4 21.8 0.107

Cannon CP, et al. N Engl J Med 2015;372(25):2387‐2397. PRIME®.



Key Takeaways from IMPROVE‐IT• Addition of a nonstatin (ezetimibe) to a moderate dose statin may lower cardiovascular event risk

• Reaffirms “lower is better” with proven risk‐reducing therapies

• Confirms safety profile of ezetimibe • No differences observed in cancer or muscle, or gallbladder‐related events

• Questions remain: • What is the optimal LDL?• How low to go?• Should guidelines be changed?

Cannon CP, et al. N Engl J Med 2015;372(25):2387‐2397. PRIME®.



Patient Case #1

• Man followed in lipid clinic for multiple decades

• PMH: HeFH, known CAD• FH: 2 brothers dying from cardiovascular causes in their 20s.

• SH: highly motivated, getting lots of exercise, trying to eat the right foods, taking 4 lipid‐lowering medications (maximum statin therapy as well as other LDL‐lowering medications )

• Despite that his LDL‐C level is 150 mg/dL

Would you consider a PCSK‐9 inhibitor in this patient?



Patient Case #2

• 40 YO Male • LDL of 110 mg/dL after maximally tolerated statin

• Recurrent CV events with multiple stents

Would you consider a PCSK‐9 inhibitor in this patient?



PCSK9 inhibitors: Sticker Shock • Evolocumab costs $14,100 per year• Alirocumab costs $14,600 per year• In Europe, PCSK9 inhibitors cost ~ $6,800 USD per year in the United Kingdom

• Every statin is available as a generic medication at a fraction of that cost

• According to ICER, the PCSK9 inhibitor price would need to come down to $2100 per year to be cost‐effective in FH patients, and to approximately $2,500 per year in the secondary‐prevention setting

Institute for Clinical and Economic Review. PCSK9 inhibitors for treatment of high cholesterol: effectiveness, value, and value‐based price benchmarks draft report. Published September 8, 2015



Statin Intolerance• Prevalence of statin‐associated muscle symptoms ranges from 7% to 29%

• In a large retrospective cohort study, 6579 of 11,124 patients who discontinued a statin due to adverse effects were rechallenged, with 92% success in restoring therapy

• Try multiple statins before labeling statin‐intolerant and considering a $14,000 alternative



Key Points• Establishing improved cardiovascular outcomes is key.• Ongoing trials are necessary for PCSK 9 inhibitors.• PCSK9 inhibitors are not for patients simply reluctant to take a statin.

• PCSK9 inhibitors are reserved for patients with “high” LDL cholesterol levels despite maximal therapy with statins and ezetimibe.



QUESTIONS

Thank You

Tran H. Tran, PharmD

[email protected]



REFERENCES• Mozaffarian D, et al. Circulation. 2015; 131(4):e29‐322; CDC. Heart Disease Facts.

www.cdc.gov/heartdisease/facts.htm. Accessed 3/24/15.

• Go AS, et al. Circulation. 2014;129(3):E28‐E292; Rosenson RS, et al. J Clin Lipidol. 2014;8(3 Suppl):S58‐S71.

• Stone NJ, et al. Circulation. 2013;129(25 Suppl 2):S1‐S45.

• Boekholdt SM, et al. J Am Coll Cardiol. 2014;64(5):485‐494.

• Lambert G, et al. J Lipid Res. 2012;53(12):2515‐2524.

• FDA News Release. FDA approves Praluent to treat certain patients with high cholesterol. Released July 24, 2015. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm

• Robinson JG, et al. N Engl J Med. 2015;372(16):1489‐1499.

• Sabatine MS, et al. N Engl J Med. 2015;372(16):1500‐1509.

• Cannon CP, et al. N Engl J Med 2015;372(25):2387‐2397.

• Institute for Clinical and Economic Review. PCSK9 inhibitors for treatment of high cholesterol: effectiveness, value, and value‐based price benchmarks draft report. Published September 8, 2015



Christopher K. Finch, Pharm.D., BCPS, FCCM, FCCPDirector of Pharmacy

Methodist University HospitalAssociate Professor

University of Tennessee, College of PharmacyMemphis, TN

October 24, 2016

Update in COPD Pharmacotherapy: Is New Better?



Conflict of Interest

• I have no conflicts of interest to disclose.



Learning Objectives

• Compare and contrast the pharmacological and cost differences with new therapy options for COPD compared to older medications.

• Discuss the evidence-based outcomes of newer pharmacologic options based on clinical trials compared to older medications.

• Explain the role of new agents in the medical management of COPD.



Abbreviations• COPD—chronic obstructive pulmonary

disease

• FEV1—forced expiratory volume in 1 second

• R—randomized

• DD—double dummy

• DB—double blind

• PC—placebo controlled

• PG—parallel group

• CAT—COPD assessment test

• mMRC—modified medical research council dyspnea scale

• GOLD—Global Initiative on Chronic Obstructive Lung Disease

• SABA—short acting beta agonist

• SAMA—short acting muscarinic antagonist

• LABA—long-acting beta agonist

• LAMA—long-acting muscarinic antagonist

• ICS—inhaled corticosteroids

• QoL—quality of life

• AUC—area under the curve

• TDI—transient dyspnea index

• PIFR—peak inspiratory flow rate



What is COPD?

A common preventable and treatable disease

Characterized by persistent airflow limitation that is usually progressive

Associated with an enhanced chronic inflammatory response in the airways and the lung

Global Initiative for Chronic Obstructive Lung Disease 2016. http://www.goldcopd.com. Accessed 8/4/16


http://www.goldcopd.com/


Epidemiology and Burden of COPD

• 24 million Americans have COPD; half don’t know it• 4th leading cause of death in the world• 2nd to heart disease as a cause of disability

• Approximately 70% of COPD patients are <65 yearsand COPD patients under the age of 65 account for:

• 52% of total hospital outpatient visits for COPD• 63% of emergency department visits for COPD• 33% of COPD Hospitalizations

• Since 2000, female deaths have exceeded male deaths

Mannino DM. Chest. 2002;121:121S-126S. Guarascio AJ et al. Clinicoecon Outcomes Res. 2013;5:235-245.AHRQ Pub No. 02-M016, March 2002. Mannino DM et al. MMWR 2002;51(SS-6):1-16.


Presenter

Presentation Notes

It is currently estimated that as many as 24 million people (including both diagnosed and undiagnosed) in the United States may have COPD. In the year 2000, 10.5 million people in the United States knew they were diagnosed with COPD, resulting in 8 million physician office and hospital outpatient visits, 1.5 million emergency room visits, 726,000 hospitalizations, and 119,000 deaths. COPD is commonly perceived as a disease of the elderly and, therefore, is not expected to have an impact on the working age population. However, according to data from the Centers for Disease Control, approximately 70% of COPD patients are under the age of 65. In addition, these patients account for 52% of all outpatient visits, 63% of all ER visits, and 33% of all hospitalizations for COPD. Thus, the impact of COPD on the working age population is substantial. In contrast to commonly held perceptions, the prevalence of COPD exceeds that of asthma in individuals age 45 to 64 years. In this population, the self-reported rate of COPD is 7.2% compared with 4.9% for asthma Adams PF et al. National Center for Health Statistics. Vital Health Stat 10(200).1999 National Heart, Lung, and Blood Institute. Data Factsheet: Chronic Obstructive Pulmonary Disease (COPD). Available at http://www.nhlbi.nih.gov/health/public/lung/other/copd_fact.html (accessed November 19, 2002).


Significant Burden Associated With Managing COPD

• Each year due to COPD, there are approximately:• 16.3 million office visits• 672,000 hospitalizations

• More than 22% of Medicare patients hospitalized for COPD in 2003–2004 were readmitted within 30 days of discharge; 36% of these readmissions were for COPD

Jencks SF et al. N Engl J Med. 2009;360:1418-1428.



Total Cost per patient per year• Annual COPD cost in 2010 was estimated at $50 billion

• Direct medical expenditures estimated $30 billion• 75% of direct costs related to exacerbations• $20 billion in indirect costs

Cost Based on Disease Progression

Guarascio AJ et al. Clinicoecon Outcomes Res. 2013;5:235-245

Stage I: $1,68131% Medication costs29% Non-medication costs

40% Hospitalization costs

Stage II: $5,037 14% Medication costs33% Non-medication costs53% Hospitalization costs

Stage III: $10,812 7% Medication costs30% Non-medication costs63% Hospitalization costs



The Major Risk Factor for COPD

• Cigarette smoking is the most important risk factor for COPD worldwide

• About 15% of smokers will develop COPD but the majority of smokers will develop loss of lung function

• Recommendation from the GOLD Guidelines:• Any current or former smoker over age 40 or never a smoker with a

family history of COPD who complains of dyspnea, chronic cough, or chronic sputum production should seek testing for COPD with spirometry

Global Initiative for Chronic Obstructive Lung Disease. www.goldcopd.com. Accessed July 2016.American Lung Association. www.lungusa.org/lung-disease/copd/resources/facts-figures/COPD-Fact-Sheet.html . Accessed July 2016.




Goals of Therapy

Global Initiative for Chronic Obstructive Lung Disease 2016. http://www.goldcopd.com. Accessed 8/4/16

Smoking cessation has the greatest capacity to

influence the natural history of COPD.

Appropriate pharmacologic therapy can reduce COPD symptoms, reduce the frequency and severity of

exacerbations, and improve health status and exercise tolerance.




COPD Assessment and Therapeutic Options

Airf

low

Lim

itatio

n(G

OLD

Cla

ssifi

catio

n)FE

V1 <

50%

pre

dict

ed

Risk

(Exa

cerb

atio

n an

d ho

spita

lizat

ion

hist

ory)

≥ 2

1

0Symptoms=CAT > 10

4

3

2

1

ICS + LABAand/orLAMA

Adapted from Global Initiative for Chronic Obstructive Lung Disease 2016. http://www.goldcopd.com. Accessed 8/4/16

A B

C D

SAMA prnor

SABA prn

LAMA or

LABA

ICS + LABAor

LAMA

Breathlessness=mMRC > 2




Short-acting bronchodilators

SABA vs SAMA

• Ipratropium vs Albuterol• Mild ↑ FEV1 and FVC• ↓ oral corticosteroids• Improve QoL scores • ↓ medication related

adverse events• NO recommendation of

one over the other

SABA/SAMA combination

• ↑ FEV1 and FVC• Similar safety profile• Similar symptom and

QoL scores• ↓ oral corticosteroids• ↓ exacerbations

Appleton S, et al. Cochrane Database of Systemic Reviews. 2006. Rennard et al. Chest. 1996;110:62-70Friedman, et al. Chest. 1999;115:635-641 Tashkin D, et al. Am J Med. 1996;100:62S-69S.



Long-acting bronchodilatorsLong-Acting Beta Agonist

• Salmeterol, Formoterol, Arformoterol• Q 12 hr dosing

• Vs. SABA• Improve compliance• ↑ FEV1 • ↓ symptoms• ↓ exacerbations• ↑ QoL

Long-Acting Muscarinic Antagonist

• Tiotropium• Qday dosing

• Vs. active comparator• UPLIFT Trial• ↑ Lung function and QoL• ↓ Dyspnea, exacerbations, and

hospital days

Mahler DA, et al. Chest. 1999;115:957-965. Brusasco V, et al. Thorax. 2003;58:399-404.Rennard SI, et al. Am J Respir Crit Care Med. 2001;163:1087-1092 Tashkin D, et al. N Engl J Med. 2008;359:1543-54



Inhaled Corticosteroids

• None have an indication for COPD as monotherapy• This isn’t asthma!

Copenhagen Euroscope Lung Health II Isolde

Pts / Length (mo) 290 / 36 912 / 36 1116 / 40 751 / 36

Med Budesonide Budesonide Triamcinolone Fluticasone

Baseline FEV1 % predicted 86% 77% 64% 46%

Exacerbations ↔ ↔ ↔ ↓

FEV1 response None None None ↑

FEV1 Decline ↔ ↔ ↔ ↔

Vestbo et al. Lancet. 1999;35:1819. Anthonisen et al. N Engl J Med. 2000;343:1902.Pauwels et al. N Engl J Med. 1999;340:1948. Burge et al. BMJ. 2000;320:1297.



ICS/LABA combinationTORCH study

Combination therapy vs LABA• ↑ FEV1• ↑ QoL• ↓ exacerbations• ↑ pneumonia

Type of trial • R,DB,PC of 6112 pts• Baseline FEV1 % predicted-44%

Intervention • Placebo• Fluticasone• Salmeterol• Fluticasone/Salmeterol combo

Primary Endpoint Mortality - ↓ 2.6% vs placebo (p=NS)

Secondary Endpoints • Exacerbations• 25% ↓ vs placebo (NNT=4)• ↓ exacerbations vs. all Tx arm (p<0.05)

• Hospitalizations• 17% ↓ vs placebo (p<0.03)

• FEV1• ↑ FEV1 vs each arm (p<0.05)

• Pneumonia• ↑ risk by 7.3% vs placebo (NNH=14)

Calverley PMA, et al. N Engl J Med 2007;356:775-89.



How do we keep up?!!!

• 10 New Drugs in 5 yearsPre-1990Albuterol Ipratropium

1990-2010TiotropiumInhaled SteroidsSalmeterol or FormoterolCombos

2011--Present11 NEW FDA meds since 2011PDE4 inhibitorsUltra LABAOnce daily ICS/LABA comboFour new LAMAFour new LABA/LAMA combos



New COPD Products

Phosphodiesterase 4 (PDE-4) inhibitor

Roflumilast—2011

Long-acting beta agonist (LABA)

Indacaterol—2011Olodaterol—2014

Long-acting muscarinic

antagonist (LAMA)Aclidinium—2012

Umeclidinium—2014Glycopyrrolate--2015

Inhaled Corticosteroid/LABA Combination

Fluticasone/vilanterol—2013

LABA/LAMA CombinationUmeclidinium/vilanterol—2013

Glycopyrrolate/indacaterol—2015Tiotropium/olodaterol—2015

Glycopyrrolate/formoterol—2016



Phosphodiesterase 4 Inhibitors



Roflumilast (Daliresp®) Medication characteristics

MOA Selectively inhibits phosphodiesterase-4 (PDE4) → accumulation of cyclic AMP (cAMP) within inflammatory and structural cells

Dose 500 mcg once daily

Pharmacokinetics • Bioavailability: ~ 80%• Metabolism: CYP3A4 and CYP1A2 to active metabolite• T1/2: 17 hours; 30 hours active metabolite• Time to peak: ~ 1 hours (delayed by food); Active metabolite ~ 8 hours • Excretion: Urine

Contraindications Moderate or severe hepatic impairment

Common side effects Weight loss, decrease appetite, diarrhea, nausea, backache, dizziness, headache, insomnia

Formulation Oral tablet

Cost $354.14 AWP, package size 30s each

Place in therapy GOLD C and DFEV1 < 50% and > 2 exacerbations/yr

http://www.azpicentral.com/daliresp/pi_daliresp.pdf. Accessed 8/12/16



Roflumilast vs Placebo• Replicate, R,DB, PC, PG x 56 weeks• Patients:

• Age > 40 with exacerbation within the past year• FEV1 % predicted < 50%• n=3091

Trial Outcomes Roflumilast Placebo Change p Value

M2-124Δ in Trough FEV1 at 56wks (mL)

45 8 37 p<0.0003

Exacerbations perpatient/year

1.08 1.27 15% p<0.0278

M2-125Δ in Trough FEV1 at 56wks (mL)

33 -25 58 p<0.05

Exacerbations perpatient/yr

1.2 1.5 18% p<0.05

Calverley PM et al. Lancet. 2009 Aug 29;374(9691):685-94.


Presenter

Presentation Notes

Has not been studied as an add-on to maximal conventional therapy


Long-acting Beta Agonists


Presenter

Presentation Notes

Relax bronchial smooth muscle by selective action on beta2 receptors locally in the lung Long duration Offer enhanced convenience No dose titration Vs. SABA Improved lung function Improved symptoms Reduced exacerbations Beneficial for nocturnal symptoms


Indacaterol (Arcapta™ Neohaler™)Medication characteristics

MOA Ultra-LABA

Dose 75 mcg inhaled once daily

Pharmacokinetics Metabolism: CYP3A4, CYP2D6, and CYP1A1T1/2: 40-56 hours Time to peak: ~15 minutes Excretion: Feces and urine

Contraindications Hypersensitivity to indacaterol or any component of the formulation

Common side effects Cough, headache, nausea, nasopharyngitis, oropharyngeal pain

Formulation Capsule, inhalation - PIFR of 52-133 L/min

Cost $256.33 AWP, package side 30s each

Place in therapy Monotherapy GOLD BCombination therapy in GOLD C and D

https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/arcapta.pdf. Accessed 8/13/16



Indacaterol vs Placebo or Twice Daily LABA

Clinical Trial Data

Indacaterol vs Placebo Indacaterol vs BID LABAType of trial Six randomized, double blinded placebo controlled

trial Meta-analysis of 4 studiesIndacaterol daily vs BID LABA’s for > 24 wks

Patients 5,474 patients with COPD• ≥ 40 years of age• History of smoking at least 10 pack years • FEV1 of at least 30% and less than 80% of

predicted

4708 patients with COPD• ≥ 40 years of age• History of smoking at least 10 pack years • FEV1 of at least 30% and less than 80% of

predicted

Outcomes • Significantly greater 24-hour post-dose trough FEV1 vs placebo

• ↑ Trough FEV1 by > 120 mL (p<0.05)• Reduced exacerbations by 31% vs

placebo

Improved:• Trough FEV1 73 mL (p<0.05)• Dyspnea 0.54 via TDI (p<0.05)No difference in:• Peak FEV1• QoL scores• Exacerbations or Mortality• Adverse effects

Kerwin EM et al. Clin Ther. 2011;33:1974. Geake JB et al. Cochrane Database of Systematic Reviews 2015, Issue 1. Art. No.: CD010139Wedzicha JA et al. Respir Med. 2015 Jan;109(1):105-11.


Presenter

Presentation Notes

Only 2 studies used the FDA approved dose of 75 mcg QD vs placebo


Indacaterol vs TiotropiumLABA vs LAMA – 14 Days

Type of trial Randomized, DB, PC, DD, crossover (n=169)

Intervention Indacaterol vs Tiotropium

Outcomes Indacaterol was at least as effective as tiotropium with a faster onset

Day 1 and 14: Both treatments with Indacaterol resulted in statistically superior FEV1 to Tio p < 0.001

LABA vs LAMA – 6 Month Duration

Type of trial R, PG study

Patients 1422 pts in GOLD A or B

Intervention Indacaterol vs Tiotropium

Outcomes ↑FEV1 30 mL; ↓ rescue SABA; dyspnea↑QoL (All p<0.05)

Vogelmeier et al. Respir Res. 2010;5(11):135.Mahler DA et al. Respir Med. 2015; 109(8);1031-1039.



Medication characteristicsMOA Long-acting Beta Agonist

Dose Two inhalations once daily (2.5 mcg/actuation)

Pharmacokinetics Bioavailability: 30%Metabolism: Direct glucuronidation and O-demethylation t1/2: 7.5 hoursTime to peak: 10-20 minutesExcretion: Feces and urine

Contraindications Patients with asthma not taking a long-term controller medication

Common side effects nasopharyngitis, skin rash, UTI, back pain, bronchitis

Formulation Aerosol Solution, inhalation

Cost $155.70 AWP

Place in therapy Monotherapy GOLD BCombination therapy in GOLD C and D

Olodaterol (Striverdi™ Respimat®)

https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203108s000lbl.pdf. Accessed 8/13/16



Olodaterol vs Placebo

80

30

80

60

110100

130 130

0

50

100

150

Trial 1 Trial 2 Trial 3 Trial 4 Trial 5 Trial 6 Trial 7 Trial 8

Chan

ge in

Tro

ugh

FEV1

(mL)



Type of trial • 8 confirmatory trials vs placebo• Replicate, R, DB, PC

Patients 3,533 COPD patients • GOLD class 2 and 3• Age > 40 yrs• 10 yr history of smoking

All p<0.05 except Trial 2

Ferguson GT et al. International Journal of COPD 2014:9 629–645https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203108s000lbl.pdf. Accessed 8/13/16


Presenter

Presentation Notes

Center watch


Olodaterol vs Formoterol or Tiotropium

131

153123

164

0

50

100

150

200

Trial 7(n=397)

Trial 8(n=439)

mL

Olodaterol5 mcg

Tiotropium5 mcg

p=NSp=NS

Koch A. et al. Int J COPD 2014:9 697–714. Lange P et al. J Pulm Respir Med 2014;4: 196

Olodaterol Formoterol

Trial 5 (n=906)

78 mL* 54 mL*

Trial 6 (n=937)

53 mL* 42 mL*

Olodaterol vs Formoterol Olodaterol vs TiotropiumType of Trial Two R, DB, DD trials Two R, DB trials

Intervention vs Formoterol 12mcg BID vs Tiotropium

Outcomes Change in Trough FEV1 from baselineSimilar profiles for all other metrics

Change in FEV1 AUC 12-24

*p<0.05 vs placebo


Presenter

Presentation Notes

P=NS vs formoterol


Long-acting AntimuscarincAntagonists



Medication characteristicsMOA Long-acting muscarinic antagonist

Dose 1 inhalation twice daily (400 mcg/actuation)

Pharmacokinetics Metabolism: Hydrolysis t1/2: 5-8 hoursTime to peak: within 10 minutes Excretion: Urine

Contraindications Severe hypersensitivity to milk proteins, aclidinium, or any of the excipients

Common side effects Headache, diarrhea, nasopharyngitis, cough

Formulation Aerosol power breath activated, inhalationMinimal PIFR of 35 L/min

Cost $301.10 AWP

Place in therapy Monotherapy GOLD BCombination therapy in GOLD C prior to steroids

Aclidinium (Tudorza® Pressair®)

http://www.azpicentral.com/tudorza/tudorza_pi.pdf. Accessed 8/13/16


Presenter

Presentation Notes

Preferred in patients with frequent exacerbations and reaches therapeutic levels within 2 days


Aclidinium vs Placebo

12472

128

0

50

100

150

ACCORD 1 ACCORD 2 ATTAIN

mL

Difference in Trough FEV1 vs Placebo

Kerwin EM et al. COPD. 2012;9:90-101. Rennard SI et al. Clin Drug Investig. 2013;33:893-904.Jones PW et al. Eur Respir J. 2012;40:830-836.

Aclidinium study

Type of Trial Randomized, double blind, placebo controlled

Patients 1,933 subjects with COPD• ≥ 40 years of age• History of smoking at least 10 pack

years • FEV1 of at least 30% and less than 80%

predicted FEV1/FVC of less than 0.7

Outcomes • Improvement in FEV1• ↓ rescue SABA use

All values p<0.05 vs placebo


Presenter

Presentation Notes

Center watch


Aclidinium vs Tiotropium

163 14399 107

0

50

100

150

200

Day 1 Day 15

Chan

ge in

mor

ning

trou

gh

FEV 1

from

bas

elin

e (m

L)

Aclid (n=29)

Tio (n=28)

p=NS p=NS

Fuhr et al. CHEST. 2012; 141(3):745-752

Aclidinium vs Active ComparatorType of Trial Randomized, DB, DD, PC, crossover

Intervention Aclidinium BID, Tio QD, placebo15 days

Outcomes Improvements in 24-h bronchodilation were comparable to Tiotropium


Presenter

Presentation Notes

used COPD symptom score definitions of Welte et al to investigate the effect of treatment on nighttime symptoms as reported daily in patient diaries.


Medication characteristicsMOA Long-acting muscarinic antagonist

Dose 1 inhalation once daily (62.5 mcg/actuation)

Pharmacokinetics Metabolism: CYP2D6t1/2: 11 hours Time to peak: 5 – 15 minutes Excretion: Feces and urine

Contraindications Severe hypersensitivity to milk proteins or any component

Common side effects Tachycardia, nasopharyngitis, upper respiratory tract infection, cough

Formulation Aerosol power breath activated, inhalationMinimal PIFR of 35 L/min

Cost $252.60 AWP


Umeclidinium (Incruse® Ellipta®)

https://www.gsksource.com/Prescribing_Information/Incruse_Ellipta/pdf/INCRUSE-ELLIPTA-PI-PIL.PDF. Accessed 8/13/16


Presenter

Presentation Notes

Preferred in patients with frequent exacerbations and longer duration of action than tiotropium (Spiriva).


Umeclidinium vs PlaceboUmeclidinium studies

Type of trial Randomized, double-blind, placebo controlled, parallel group trials• 24-week placebo controlled trial • 12 week placebo controlled trial

Patients n=1,738 pts• 10 yr history of smoking• FEV1 < 70% predicted• FEV1/FVC < 0.70

Outcomes • Mean ↑ in Trough FEV1 of 127 mL (p<0.05)• QoL scores improved 30%

Trivedi R et al. Eur Respir J. 2014;43:72–81https://www.gsksource.com/Prescribing_Information/Incruse_Ellipta/pdf/INCRUSE-ELLIPTA-PI-PIL.PDF. Accessed 8/13/16


Presenter

Presentation Notes

Center watch


Umeclidinium vs other LAMA’s

95154

123 99

050

100150200

Tio/Umec(n=1017)

Umec/Glyc(n=1034)

ΔTr

ough

FEV

1 (m

L) fr

om

base

line

Tiotropium 18 mcg Qday

Umeclidinium 62.5 mcg Qday

Glycopyrronium 44mcg Qday

p<0.001

Feldman et al. Int J Chron Obstruct Pulmon Dis. 2016. 7;11:719-30https://clinicaltrials.gov/ct2/show/study/NCT02236611?sect=X70156. Accessed 8/11/16

p=NS

Umeclidinium vs Tiotropium Umeclidinium vs Glycopyrronium

Type of trial R, B, DD, PG x 12 wks R, Open label, PG x 12 wks

Patients • Age > 40• GOLD 2 and 3 with mMRC > 2

• Age > 40• GOLD 2 and 3 with mMRC > 2



Glycopyrrolate (Seebri™ Neohaler®)Medication characteristics

MOA Long-acting muscarinic antagonist

Dose 1 inhalation twice daily (15.6 mcg/actuation)

Pharmacokinetics Metabolism: multiple CYP enzymest1/2: 33-43 hours Time to peak: 5 minutes Excretion: Feces and urine

Contraindications Hypersensitivity to glycopyrrolate or to any of the ingredients

Common side effects Sinusitis, nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, urinary tract infection

Formulation Capsule, inhalation PIFR of 52-133 L/min

Cost $ 297.80 AWP


https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/seebri.pdf. Accessed 8/13/16.



Glycopyrrolate vs Placebo

139 12311586

0

50

100

150

GEM 1 GEM 2

mL

Difference in FEV1 AUC0-12 and Trough FEV1 from Placebo

FEV1 AUC0-12 Trough FEV1

LaForce C et al. Int J of Chron Obst Pulmon Dis. 2016 Jun 8;11:1233-43Kerwin E et al. Chronic Obstr Pulm Dis (Miami). 2016; 3(2): 549-559

Glycopyrrolate study

Type of Trial Randomized, double blind, placebo controlled, parallel group x 12 wks

Patients 867 subjects with COPD• ≥ 40 years of age• History of smoking at least 10

pack years • FEV1 of at least 30% and less than

80% predicted • mMRC > 2

Outcomes • Improvement in FEV1• ↓ rescue SABA use • ↑ QoL and dyspnea scores

All values p<0.05


Presenter

Presentation Notes

Center watch


Glycopyrrolate vs Indacaterol

56 60

0

20

40

60

80

Day 1

(mL)

Change in morning trough FEV1 from baseline

Glycopyrrolate (n=254)

Indacaterol (n=257)

p=NS

Mahler DA et al. Respiratory Medicine, 2016;115:39-45

Aclidinium vs Active ComparatorType of Trial Randomized, DB, PC study x 52 weeks (GEM 3 Study)

Intervention Glycopyrrolate 15.6 mcg INH BID vs Indacaterol 75 mcg INH daily

Outcomes Improvements in 24-h bronchodilation were comparableIndacaterol reduced SABA use vs Glycopyrrolate (p<0.05)Safety was comparable



Inhaled Corticosteroid/Long-acting Beta Agonist Combination


Presenter

Presentation Notes

MOA: ICS– corticosteroid, LABA– selectively acts on beta2 receptors ICS – concern for increased risk of pneumonia Only recommended for patients with severe impairments and high risk for exacerbations More effective in frequent exacerbations with chronic bronchitis Cazzola 2014


Medication characteristicsMOA Inhaled corticosteroid and long-acting beta agonist combination

Dose 1 inhalation once daily (100mcg/25mcg per actuation)

Pharmacokinetics Metabolism: CYP3A4t1/2: ~24 hours Time to peak: Fluticasone < 1 hr/ Vilanterol 10 minExcretion: Feces and Urine

Contraindications Primary treatment of acute asthma or COPD exacerbationSevere hypersensitivity to milk proteins or any ingredients

Common side effects Cough, headache, nausea, nasopharyngitis, oropharyngeal pain

Formulation Aerosol power breath activated, inhalation PIFR 43-81 L/min

Cost $267.00 AWP, package size 60 blisters

Place in therapy GOLD C (potentially after LABA/LAMA combo)

https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Anoro_Ellipta/pdf/ANORO-ELLIPTA-PI-MG.PDF. Accessed 8/13/16

Fluticasone/vilanterol(Breo® Ellipta®)


Presenter

Presentation Notes

Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. selectivity of vilanterol was similar to salmeterol.


Fluticasone/vilanterol Lung Function and Exacerbation Trials

Martinez FJ et al. Respir Med. 2013; 107: 550-559Kerwin EM et al. Respir Med. 2013;107(4):560-569 Dransfield MT et al. Lancet Resp Med. 2013;1(3):210-223.

45 48

144115

0

50

100

150

200

Trial 1 Trial 2

Chan

ge in

Tr

ough

FEV

1 (m

L)

VIFF/VI 100

p<0.05 vs placebo onlyAnnual Rate of Exacerbations

FF/VI Vilanterol % Change(*p<0.05)

Trial 3 (n=1622)

0.90 1.14 ↓21%*

Trial 4(n=1633)

0.70 1.05 ↓34%

Lung Function Studies• Replicate, R DB, PC, PG, 24 wks• n=2,254• Mean FEV1 % predicted is 48%

Exacerbation Studies

• Replicate, R, DB, PG, 52 wks• n=3,255• Mean FEV1% predicted is 45%


Presenter

Presentation Notes

Center watch


Long-acting Beta Agonist/Long-acting

Muscarinic Antagonist Combination


Presenter

Presentation Notes

Tiotropium/Salmeterol via separate devices n=95 Compared to individual components ↑ FEV1 > 100 ml* ↑ FVC > 170 ml* ↓ dyspnea* ↓ rescue SABA* Similar safety profile This set the stage for a combination product!! Van Noord JA, et al. Respir Med. 2010;104(7):995-1004. Leverage different receptor types at submaximal doses Minimize dose dependent side effects Decrease complexity Combination results in significantly greater improvements in: Lung function Dyspnea Symptom scores Rescue medication use Health status and QoL Exacerbations Nocturnal symptoms and those present on awakening


Medication characteristicsMOA Long-acting muscarinic antagonist and long-acting beta agonist combination

Dose 1 inhalation once daily (62.5 mcg/25 mcg per actuation)

Pharmacokinetics Metabolism: CYP2D6 (umec) and CYP3A4 (vil) t1/2: 11 hoursTime to peak:Excretion: Urine and feces

Contraindications Severe hypersensitivity to milk proteins or any ingredients

Common side effects Diarrhea, pharyngitis, chest pain

Formulation Aerosol power breath activated, inhalation PIFR 43-81 L/min

Cost $315.70 AWP, package size 60 blisters

Place in therapy GOLD B after failure of monotherapy or GOLD C

https://www.gsksource.com/Prescribing_Information/Anoro_Ellipta/pdf/ANORO-ELLIPTA-PI-MG.PDF. Accessed 8/13/16

Umeclidinium/vilanterol(Anoro® Ellipta®)


Presenter

Presentation Notes

selectivity of vilanterol was similar to salmeterol.


Umeclidinium/Vilanterol Clinical TrialsDonohue et al Decramer et al

Type of trial Randomized, DB, PC, PG over 24 wks Replicate, Randomized, blind, DD, PG, 24 wks

Intervention Combo, UMEC 62.5 mcg, VI 25 mcg, placebo

Umec/VI vs Tiotropium

Patients n=1,532 mMRC ≥ 2

Decramer 1- n=846Decramer 2- n=872

Outcomes • FEV1 +52 mL versus 95 mL and 167 mL respectively (p<0.05)

• Dyspnea and QoL similar in all groups

• ↓ exacerbations

Cohen JS et al. Int J COPD. 2016;11:785-797. Decramer M et al. Lancet Respir Med. 2014;2(6):472-486Donohue JF et al. Respir Med. 2013;107(10):1538-1546.

No difference for QoL, symptoms, and exacerbations




Dose 1 capsule inhaled twice daily (27.5 mcg/15.6 mcg per actuation)

Pharmacokinetics Metabolism: multiple CYP enzymes t1/2: ~53 hours Time to peak: 5-15 minutes Excretion: Feces and Urine

Contraindications Asthma without use of a long-term controller medicationHistory of known hypersensitivity to indacaterol, glycopyrrolate.

Common side effects Nasopharyngitis, Rhinitis, hypertension, headache, diarrhea, GERD

Formulation Capsule, inhalation PIFR of 52-133 L/min

Cost $297.80 AWP


https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/utibron.pdf. Accessed 8/13/16

Indacaterol/Glycopyrrolate(Utibron™ Neohaler®)


Presenter

Presentation Notes



Indacaterol/Glycopyrrolate vs Active ComparatorSHINE SPARK ILLUMINATE

Type of trial R, DB, PC, PG R, DB, PG R, DB, DD

Intervention • Inda/Gly vs Tiotriopium• 26 wks

• Inda/Gly vs Tiotriopium• 64 wks

• Inda/Gly vs Salmeterol/fluticasone• 26 wks

Patients FEV1 % Predicted of 30-80% FEV1 < 50% with > 1 exacerbation FEV1 % Predicted of 30-80%

Take Home: Improvements in FEV1, QoL, symptoms, rescue SABA, and exacerbations *NOTE: ALL studies conducted with higher than FDA approved dose

Cohen JS et al. Int J COPD. 2016;11:785-797. Bateman ED et al. Eur Respir J 2013;42:1484-1494.Wedzicha J et al. Lancet Respir Med. 2013;1:199-209. Vogelmeier CF et al. Lancet Respir Med. 2013;1:51-60.

12080

200150

295

0

157

050

100150200250300350

SHINE(n=2,144)

SPARK(n=2,224)

ILLUMINATE(n=523)

Chan

ge in

Tro

ugh

FEV1

(m

L)

TiotropiumInda/GlycoSalm/flut

p<0.05 for all

Δ 80 mL

Δ 70 mL

Δ 138 mL



FLAME StudyIndacaterol/Glycopyrrolate vs Salmeterol/Fluticasone

Type of trial R, DB, DD, PG, non-inferiority, multi-center, 52 wks

Intervention Indacaterol/Glycopyrrolate 110/50 mcg QdaySalmeterol/Fluticasone 50/250 mcg bid

Patients n=3,362Age > 40FEV1 % predicted 25-60%mMRC > 2

Indacaterol/Glycopyrrolate

Salmeterol/Fluticasone

p value

Primary OutcomeExacerbations/yr 3.59 4.03 0.003

Secondary Outcomes

Time to first exacerbation 71 days 51 days <0.001Incidence of pneumonia 3.2% 4.8% 0.02Change in Trough FEV1 from baseline

15 mL -48 mL <0.001

Wedzicha JA et al. N Engl J Med 2016;374:2222-34.




Dose Two inhalations once daily (2.5 mcg/2.5 mcg per actuation)

Pharmacokinetics Metabolism: multiple CYP enzymest1/2: 25-45 hours Time to peak: 5-10 minutes Excretion: Feces and Urine

Contraindications Patients with asthma without a controller medication Hypersensitivity to tiotropium, ipratropium, olodaterol

Common side effects Nasopharyngitis and cough

Formulation Aerosol solution, inhalation

Cost $315.70 AWP


http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Stiolto%20Respimat/stiolto.pdf. Accessed 8/13/16

Tiotropium/olodaterol(Stiolto® Respimat®)


Presenter

Presentation Notes



Tiotropium/Olodaterol vs Individual Components

Buhl R et al. Eur Respir J 2015; 45: 869–871

TOnado 1 and 2Type of trial Randomized, double-blind, parallel group Outcomes

Intervention • Treatment groups (daily dose) • T/O 2.5/5 mcg• T/O 5/5 mcg• TIO 2.5 mcg• TIO 5 mcg• OLO 5 mcg

• 52 weeks

Patients • 5,163 COPD patients • ≥ 40 yrs old• Smoking history of > 10 pack-

years• Moderate to very severe

pulmonary impairment • ↑ FVC and QoL• ↓ rescue SABA and exacerbations


Presenter

Presentation Notes

Center Watch , Cohen


ENERGITO Study

Type of trial Randomized , double-blind, double-dummy with four 6 wktreatment arms, each followed by 3 wk washout

Patients n=220 pts• 10 yr history of smoking• FEV1/FVC < 0.70• GOLD Class 2 and 3

Adjusted Mean FEV1 AUCTio/Olo 2.5/2.5 Salmeterol/Fluticasone

50/250Difference

FEV1 AUC (0-12hrs) 317 mL 192 mL 125 mL*

FEV1 AUC (12-24hrs) 172 mL 132 mL 40 mL*

Conclusion Improved lung function and hyperinflation at all time pointsBeeh KM et al. Int J COPD. 2016;11:193-205

Tiotropium/Olodaterol vs Salmeterol/Fluticasone

*p<0.05




Dose Two inhalations twice daily (9mcg/4.8 mcg per inhalation)

Pharmacokinetics Metabolism: CYP2D6 and CYP2Ct1/2: 11.8 hours Time to peak: 5-20 minutes Excretion: Feces and Urine

Contraindications Patients with asthma without use of a long-term control medicationHypersensitivity to glycopyrrolate, formoterol, or any component

Common side effects Nasopharyngitis and cough

Formulation Aerosol, inhalation

Cost Not available


http://www.azpicentral.com/bevespi/bevespi_pi.pdf. Accessed 8/13/16

Glycopyrrolate/formoterol (Bevespi Aerosphere™)


Presenter

Presentation Notes

Co-suspension Porous, low-density phospholipid particles designed to form a uniform suspension inside the pMDI and more uniform drug distribution throughout the lungs Stable, homogeneous suspension Future use: Fixed-dose triple combination of LAMA/LABA/Inhaled corticosteroid


Glycopyrrolate/formoterol vs Individual Components

PINNACLE 1 and 2Type of trial Replicate, randomized, double-blind,

placebo controlled, parallel groupOutcomes

Intervention • Treatment groups (2 puffs bid)• Gly/For 9/4.8 mcg• Gly 9 mcg• For 4.8 mcg• Placebo

• 24 weeks

Patients • 3,699 COPD patients • ≥ 40 yrs old• Smoking history of > 10 pack-

years• Moderate to very severe

pulmonary impairment

150

103

59 5464 56

0

20

40

60

80

100

120

140

160

PINNACLE 1 PINNACLE 2

mL

Change in Trough FEV1

Gly/For vsPlacebo

Gly/For vs Gly

Gly/For vs For

http://www.azpicentral.com/bevespi/bevespi_pi.pdf. Accessed 8/13/16


Presenter

Presentation Notes

Center Watch , Cohen


So, which agent do we choose?

Too many choices!

Disease assessment Cost

Delivery system Adherence



Disease AssessmentAi

rflo

w L

imita

tion

(GO

LD C

lass

ifica

tion)

FEV1

< 5

0% p

redi

cted

Risk

(Exa

cerb

atio

n an

d ho

spita

lizat

ion

hist

ory)

≥ 2

1

0Symptoms=CAT > 10

4

3

2

1

ICS + LABAand/orLAMA

Adapted from Global Initiative for Chronic Obstructive Lung Disease 2016. http://www.goldcopd.com. Accessed 8/4/16

A B

C D

SAMA prnor

SABA prn

LAMA or

LABA

LABA/LAMAor

ICS/LABA

Breathlessness=mMRC > 2




Drug Formulation Dosage Wholesale CostLong-Acting Muscarinic Antagonist

Tiotropium 18 mcg/cap DPI2.5 mcg/inh ISI

1 inh Qday2 inh Qday

$315.70

Aclidinium 400 mcg/inh DPI 1 inh bid $301.10

Glycopyrrolate 15.6 mcg/cap DPI 1 inh bid $297.80

Umeclidinium 62.5 mcg/inh DPI 1 inh Qday $252.60

Long-Acting Beta Agonist

Salmeterol 50 mcg/blister DPI 1 inh bid $322.60

Formoterol 1 inh bid $251.00

Indacaterol 75 mcg/cap DPI 1 inh Qday $213.60

Olodaterol 2.5 mcg/inh ISI 2 inh Qday $155.70

Long Acting Beta Agonist/Long Acting Muscarinic Antagonist Combo

Glycopyrrolate/Indacaterol 15.6/27.5 mcg/cap DPI 1 inh bid $297.80

Tiotropium/Olodaterol 2.5/2.5 mcg/inh ISI 2 inh Qday $315.70

Umeclidinium/vilanterol 62.5/25 mcg/blister DPI 1 inh Qday $315.70

Glycopyrrolate/formoterol 9/4.8 mcg/inh MDI 2 inh bid Not available

Inhaled Corticosteroid/Long-Acting Beta Agonist

Fluticasone Furoate/Salmeterol 100/25 mcg/blister DPI 1 inh Qday $267.00



Delivery SystemsType Advantages Disadvantages

Nebulizer • Patient coordination not required• Tidal breathing

• Device cleaning required • Expensive• Contamination possible• Not all medication available in solution

formPressurizedmetered dose inhaler

• Portable and compact• Treatment time is short• No drug preparation required• Dose-dose reproducibility high

• Coordination of breathing and actuation needed

• Necessary hand strength• High pharyngeal deposition

Dry powder inhaler

• Breath-actuated• Less coordination required• Small and portable• Short treatment time• Dose counters

• Requires moderate to high inspiratory flow

• Some units are single dose (capsules)• Can result in high pharyngeal deposition

Soft mist inhalers

• Similar to neb but more convenient

• Lower pharyngeal deposition• 1/3 the actuation rate of MDI

• High cost• Some coordination required• Limited products

Barrons R et al. Patient Intelligence. 2015;7:53-65.


Presenter

Presentation Notes

Holding chamber or spacer ADVANTAGES Reduces need for patient coordination Reduces pharyngeal deposition DISADVANTAGES Inhalation can be more complex for some patients Can reduce dose available if not used properly More expensive than MDI alone More bulky than MDI alone


Adherence

“Drugs don’t work in patients that don’t take them”

• 60% of COPD pts nonadherent• Nonadherence leads to:

• ↑ exacerbations, hospitalizations and mortality

• Reasons:• # of meds and dosing frequency contribute significantly• Cost

Restrepo RD et al. Int J Chron Obstruct Pulmon Dis. 2008;3(3):371-384.Agh T et al. Respiration. 2011;82,(4):328–34.Agh T. http://www.intechopen.com/books/chronic-obstructive-pulmonarydisease-current-concepts-and-practice/adherence-to-therapy-in-chronic-obstructive-pulmonary-disease. Accessed 8/14/16

C. Everett Koop, M.D.



Ideal Therapy for COPD Adherence

Ease of administration

DyspneaExacerbations

Exercise Tolerance

Quality of LifeMortality

HospitalizationsOverall Cost



Christopher K. Finch, Pharm.D., BCPS, FCCM, FCCPDirector of Pharmacy

Methodist University HospitalAssociate Professor

University of Tennessee, College of PharmacyMemphis, TN

October 24, 2016

Update in COPD Pharmacotherapy: Is New Better?


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